Semi-synthetic desmethyl-vancomycin-based glycopeptides with antibiotic activity

Abstract

Semi-synthetic glycopeptides that have antibacterial activity are based on modifications of the desmethyl-vancomycin scaffold, in particular, acylation of the amino substituent on the amino-substituted sugar moiety on this scaffold with certain acyl groups; and/or conversion of the acid moiety on the macrocyclic ring of this scaffolds to certain substituted amides. In addition, compounds of the invention include desmethyl-vancomycin scaffolds on which the acid moiety on the macrocyclic ring is converted to certain substituted amides and the amino substituent on the amino-substituted sugar moiety is alkylated with certain alkyl groups. Also provided are methods for synthesis of the compounds, pharmaceutical compositions containing the compounds, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.

1 . A compound having a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is C(═O)CR 7 R 7a NR 8 R 8a , wherein,  
 R 7  and R 7a  are independently hydrogen, the side chain of a naturally occurring or non-naturally occurring amino acid, alkyl, or alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, alkoxyalkoxy, carboxyl, carboxyl ester, —C(═O)NR 8 R 8a , —NR 8 R 8a , aryl, substituted aryl, heteroaryl, substituted heteroaryl, mercapto, or thioalkoxy, or R 7  and R 7a  together with the atom to which they are attached form a cycloalkyl ring which optionally contains a heteroatom selected from the group consisting of optionally substituted O, N, and S;  
 R 8  and R 8a  are independently selected from the group consisting of hydrogen and unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl, said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one or more optionally substituted aryl, heteroaryl, or condensed rings, or R 8  and R 8a  together with the atom to which they are attached form a cycloalkyl ring which optionally contains a heteroatom selected from the group consisting of optionally substituted O, N, and S; 
 R 1A  is selected from the group consisting of H, CHR 5 R 5a , and C(═O)R 6 , wherein,  
 
 R 5  and R 5a  are independently selected from the group consisting of hydrogen and unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl, said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one or more optionally substituted aryl, heteroaryl, or condensed rings, or R 5  and R 5a  together with the atom to which they are attached form a cycloalkyl ring which optionally contains a heteroatom selected from the group consisting of optionally substituted O, N, and S, and  
 R 6  is selected from the group consisting of unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl containing a heteroatom selected from the group consisting of optionally substituted O, N, and S, said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one or more optionally substituted aryl, heteroaryl, or condensed rings; 
 R 2  is selected from the group consisting of, 
 (1) OH,  
 (2) 1-adamantanamino,  
 (3) 2-adamantanamino,  
 (4) 3-amino-1-adamantanamino,  
 (5) 1-amino-3-adamantanamino,  
 (6) 3-loweralkylamino-1-adamantanamino,  
 (7) 1-loweralkylamino-3-adamantanamino,  
 (8) amino,  
 (9) NR 9 R 9a  wherein R 9  and R 9a  are independently selected from the group consisting of hydrogen, loweralkyl or substituted lowerakyl, or 
 R 9  and R 9a  together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, which may optionally be substituted with one or more substituents independently selected from the group consisting of  
 (a) halogen,  
 (b) hydroxy,  
 (c) C 1 -C 3 -alkoxy,  
 (d) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy,  
 (e) oxo,  
 (f) C 1 -C 3 -alkyl,  
 (g) halo-C 1 -C 3 -alkyl, and  
 (h) C 1 -C 3 -alkoxy -C 1 -C 3 -alkyl;  
 
 
 R 2 A is selected from the group consisting of 
 (1) 1-adamantanamino,  
 (2) 2-adamantanamino,  
 (3) 3-amino-1-adamantanamino,  
 (4) 1-amino-3-adamantanamino,  
 (5) 3-loweralkylamino-1-adamantanamino,  
 (6) 1-loweralkylamino-3-adamantanamino; and  
 
 R 3  is selected from the group consisting of hydrogen and aminoloweralkyl, wherein the aminoloweralkyl amino group is further substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, alkylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer or prodrug thereof.  
 
 
     
     
         2 . The compound of  claim 1 , wherein R 5  is hydrogen and R 5a  is selected from the group consisting of unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl, said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one or more optionally substituted aryl, heteroaryl, or condensed rings, or R 5  and R 5a  together with the atom to which they are attached form a cycloalkyl ring which optionally contains a heteroatom selected from the group consisting of optionally substituted O, N, and S.  
     
     
         3 . The compound of  claim 2 , wherein R 5a  is unsubstituted biphenyl.  
     
     
         4 . The compound of  claim 3 , wherein R 5a  is a halogen-substituted biphenyl.  
     
     
         5 . The compound of  claim 4 , wherein R 5a  is chloro-biphenyl.  
     
     
         6 . The compound N′-p-C 8 H 17 OBnHNCH 2 CO desmethyl-vancomycin.  
     
     
         7 . The compound N′-p-C 8 H 17 OBnHNCH(CH 3 )CO desmethyl-vancomycin  
     
     
         8 . The compound of  claim 1 , wherein R 6  is a β-amino acid analog comprising a —CH 2 CHNH— portion.  
     
     
         9 . The compound of  claim 8 , wherein R 6  is selected from the group consisting of CH2C(R 7 )(R 7a )(NR 8 R 8a ) wherein R 7 , R 7a , R 8 , and R 8a  are previously defined or —CR 7 R 7a  together with NR 8 R 8a  form a pyrrolidine ring.  
     
     
         10 . The compound of  claim 1 , wherein C(═O)CR 7 R 7a NR 8 R 8a  is selected from the group consisting of amino acid moieties.  
     
     
         11 . The compound of  claim 10 , wherein R 7 , R 8  and R 8a  are each H and R 7a  is selected from the group consisting of H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , (CH 2 ) 4 NH 2 , CH 2 OH, CH(OH)CH 3 , CH 2 COOH, (CH 2 ) 2 COOH CH 2 C(═O)NH 2 , (CH 2 ) 2 C(═O)NH 2 , CH 2 SH, (CH 2 ) 2 SCH 3 , (CH 2 ) 3 NHC (═NH)NH 2 , CH 2 C 6 H 5 , CH 2 C 6 H 4 0H, CH 2 (4-imidazoyl) and CH 2 (3-indolyl), or —CR 7 R 7a  together with NR 8 R 8a  form a pyrrolidine ring.  
     
     
         12 . The compound of  claim 1 , wherein R 7  is H and R 7a  is selected from the group consisting of 
 (1) hydrogen,    (2) C 1 -C 12 -alkyl, and    (3) C 1 -C 12 -alkyl substituted with one or more substituents selected from the group consisting of 
 (a) halogen,  
 (b) hydroxy,  
 (c) C 1 -C 3 -alkoxy,  
 (d) C 1 -C 3 -alkoxy-C-C 3 -alkoxy,  
 (e) —CO 2 R 5  wherein R 5  is hydrogen, loweralkyl or substituted loweralkyl,  
 (g) amino, and  
 (h) —NR 9 R 9a , or 
 R 9  and R 9a  together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of  
 (i) halogen.  
 (ii) hydroxy,  
 (iii) C 1 -C 3 -alkoxy,  
 (iv) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy,  
 (v) oxo,  
 (vi) C 1 -C 3 -alkyl,  
 (vii) halo-C 1 -C 3 -alkyl, and  
 (viii) C 1 -C 3 -alkoxy -C 1 -C 3 -alkyl,  
 
 (i) aryl,  
 (j) substituted aryl,  
 (k) heteroaryl,  
 (l) substituted heteroaryl,  
 (m) mercapto, and  
 (n) C 1 -C 3 -thioalkoxy.  
   
     
     
         13 . The compound of  claim 1 , wherein R 8  and R 8a  are independently selected from the group consisting of, 
 (1) hydrogen,    (2) C 1 -C 12 -alkyl,    ( 3) C 2 -C 12 -alkyl substituted with one or more substituents selected from the group consisting of 
 (a) halogen,  
 (b) hydroxy,  
 (c) C 1 -C 3 -alkoxy,  
 (d) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy,  
 (e) amino, and  
 (f) C 1 -C 3 -alkylamino,  
   (4) C 1 -C 12 -alkyl substituted with aryl,    (5) C 1 -C 12 -alkyl substituted with substituted aryl,    (6) C 1 -C 12 -alkyl substituted with heteroaryl, and    (7) C 1 -C 12 -alkyl substituted with substituted heteroaryl; or    R 8  and R 8a  together with the atom to which they are attached form a C 3 -C 7 -heterocycloalkyl ring which, when the ring is a 5- to 7- membered ring, optionally contains a hetero function selected from the group consisting of —O—, —NH, —N(C 1 -C 6 -alkyl-)-, —N(aryl)-, —N(aryl-C 1 -C 6 -alkyl-)-, —N(substituted-aryl-C 1 -C 6 -alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C 1 -C 6 -alkyl-)-, —N(substituted-heteroaryl-C 1 -C 6 -alkyl-)-, and —S— or S(═O) n — wherein n is 1 or 2.    
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , together with a pharmaceutically acceptable carrier.  
     
     
         15 . A method of treating a mammal in need of such treatment comprising administering to the mammal an antibacterially effective amount of a compound of  claim 1  together with a pharmaceutically acceptable carrier.  
     
     
         16 . A method of making a compound of  claim 1 , comprising: 
 modifying a desmethyl-vancomycin scaffold,                          by a technique selected from the group consisting of, 
 (a) acylation of the amino substituent on the amino-substituted sugar moiety of the compound with an acyl group having the structure, 
   —C(═O)CR 7 R 7a NR 8 R 8a , 
 (b) conversion of the acid moiety on the macrocyclic ring of the compound with a substituted amide as defined by R 2 , and  
 (c) a combination of (a) and (b)  
 (d) a combination of (b) and acylation of the amino substituent on the amino-substituted sugar moiety of the compound with an acyl group having the structure, 
   —C(═O)R 6 , 
 (e) a combination of (b) and alkylation of the amino substituent on the amino-substituted sugar moiety of the compound with an alkyl group having the structure, 
   CHR 5 R 5a , 
 to form a compound having a formula selected from the group consisting of:  
                     
 wherein R 1 , R 1A , R 2 , R 2A , R 3 , R 5 , R 5a , R 6 , R 7 , R 7a , R 8 , and R 8a  are as defined herein.